Chronic Obstructive Pulmonary Disease (COPD), including emphysema and chronic bronchitis, is the fourth leading cause of death in the US, accounting for 120,000 fatalities annually. It is the only leading cause of death with rising mortality, with death rate increasing 67% between 1980 and 2000. While 14 million Americans are diagnosed with COPD, an estimated 20 million additional sufferers remain undiagnosed. The yearly economic burden of COPD is estimated at 35 billion US$. An FDA-approved functional magnetic resonance imaging (MRI) agent would provide greater specificity for disease diagnosis and phenotyping, would assist in delivering more personalized medicine to individuals, and would offer greater statistical significance to pharma companies conducting drug trials. Unlike CT, MRI uses no ionizing radiation so it can be used repeatedly. Hyperpolarized gas MRI offers exquisite detail in assessments of lung functional microstructure and microstructural changes associated with emphysema. Diffusion-weighted imaging yields regional maps of Apparent Diffusion Coefficient (ADC) which is sensitive to whether alveolar septa are intact. While ADC measurements have been demonstrated successfully using both 129Xe and 3He, only xenon can directly sense the presence of these gas exchange membranes. Our group is the first to demonstrate Xenon magnetization Transfer Contrast (XTC) in humans. By repeatedly manipulating the 129Xe magnetization dissolved in the tissues and allowing those spins to modify the polarization of the gas phase, XTC offers unparalleled sensitivity to local gas exchange surface area. Furthermore, since 129Xe is abundant in nature only xenon offers a commercially viable strategy for widespread clinical imaging of lung microstructure. Xemed has secured FDA approval for human subject testing, completed Phase 1 trials and advanced to Phase 2, and is committed to completing the regulatory process and securing New Drug status for its signature imaging agent MagniXene}. In this Phase 2 proposal we will extend our ADC and XTC protocols in quantitative precision, application versatility, and diagnostic relevance. Our investigation of two protocol refinements added to the two we already implemented in Phase 1 will assure high reproducibility and internal crosschecks. All protocols will be optimized for the present 2D projections and 1D histograms, as well as for new 2D slices and 3D renderings. ADC studies will be extended to include stimulated echo studies, which may provide sensitivity to changes in collateral ventilation, enhancing diagnosis of early emphysema. XTC studies will be extended to compare short and long gas exchange times, with sensitivity to septal wall thickening and blood flow. Voxel-by-voxel reproducibility studies will be performed. Parameters will be optimized on healthy volunteers and patients with mild to moderate lung disease. This study, the first component of our Phase 2 FDA trial program, will standardize biomarkers for emphysema, leading to a large-scale Phase 2 FDA clinical trial of MagniXene} as a safe, effective, and commercially viable imaging agent for pulmonary disease. [unreadable] [unreadable] [unreadable]